Keeping Cancer in Check:
Penn Researchers Demonstrate that a Metabolic Enzyme
Works Through the Tumor-Suppressor Protein p53
to Control Cellular Replication

(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have identified
in normal cells that a common metabolic enzyme, which
acts as a rheostat of cellular conditions, also controls
cell replication. This control is managed through p53,
the much-studied protein implicated in many types of
cancer. The discovery of the interaction between these
two molecules may lead to new ways to fight cancer.
First author Russell G. Jones, PhD,
a postdoctoral fellow in the laboratory of senior author
Craig Thompson, MD, at the Abramson
Family Cancer Research Institute at Penn, and
colleagues describe their findings in the most recent
issue of Molecular Cell.

This work tests the novel notion that cancer cells co-opt
cellular pathways that govern metabolism in order to
proliferate beyond a cell’s normal means. Cancer
cells have, by definition, a high metabolic rate and
consume glucose at a high rate. One of the fundamental
questions being tested in the Thompson lab is the importance
of metabolism in cancer and investigating how cancer
cells differ from normal cells, allowing them to survive
and replicate. (Thompson is the Chair of Penn’s
Department of Cancer Biology and Scientific Director
of the Abramson Family Cancer Research Institute.)

“We think that the enzyme interprets the energetic
environment of the cell,” explains Jones. “It
senses the stress a cell sees - such as low oxygen,
low glucose, or the presence of free radicals - and,
from this, can induce a check on replication through
p53, acting in effect as a tumor-suppressor.”

For this study, the investigators looked at noncancerous
mouse cells called fibroblasts to see how normal cells
work and what they do physiologically when faced with
an environmental challenge: in this case, low glucose
levels, explains Jones.

When the enzyme - called AMP-activated protein kinase
(AMPK) - is turned on, it prevents cells from replicating.
It acts as a sensor to detect energy levels in a cell.
When the cell experiences energy-limiting conditions,
which is typified by low glucose, it uses more energy
than it produces and enters into an energy-deficit state.
In essence, AMPK acts as a “fuel gauge,”
letting a cell know when glucose levels are dangerously
low. When AMPK is activated by low glucose levels, it
stops cells from replicating.

But how is p53 implicated? Normally p53 is activated
in response to stress, and it stops a cell from replicating
through a complicated set of biochemical steps. For
example, if a cell is hit by radiation, enzymes called
kinases activate p53, leading to inhibition of cell
replication. “We found that cells without p53
due to a mutation would continue to proliferate under
low glucose conditions, bypassing the AMPK checkpoint,”
says Jones. The lab is now doing follow-up studies and
is finding that when AMPK is activated in a tumor cell
that has no active p53, it still proliferates, escaping
the AMPK checkpoint. This avenue of study may one day
provide another approach to treating cancer, the researchers
surmise.

The study was funded in part by the National Institutes
of Health. Study co-authors are David R. Plas, Sara
Kubek, and Monica Buzzai from Penn, as well as Morris
J. Birnbaum and James Mu from the Howard Hughes Medical
Institute at Penn, and Yang Xu from the University of
California, San Diego.

The Abramson Cancer Center of the University
of Pennsylvania was established in 1973 as
a center of excellence in cancer research, patient care,
education and outreach. Today, the Abramson Cancer Center
ranks as one of the nation’s best in cancer care,
according to U.S. News & World Report, and is one
of the top five in National Cancer Institute (NCI) funding.
It is one of only 39 NCI-designated comprehensive cancer
centers in the United States. Home to one of the largest
clinical and research programs in the world, the Abramson
Cancer Center of the University of Pennsylvania has
275 active cancer researchers and 250 Penn physicians
involved in cancer prevention, diagnosis and treatment.

PENN Medicine is a $2.7 billion
enterprise dedicated to the related missions of medical
education, biomedical research, and high-quality patient
care. PENN Medicine consists of the University of Pennsylvania
School of Medicine (founded in 1765 as the nation’s
first medical school) and the University of Pennsylvania
Health System.

Penn’s School of Medicine is ranked #3 in the
nation for receipt of NIH research funds; and ranked
#4 in the nation in U.S. News & World Report’s
most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its
superior education and training of the next generation
of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital,
the Hospital of the University of Pennsylvania, consistently
rated one of the nation’s “Honor Roll”
hospitals by U.S. News & World Report; Pennsylvania
Hospital, the nation's first hospital; Presbyterian
Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities;
and home health care and hospice.